Fig. 5.

BCN057 does not have any radioprotective effect on colonic tumor tissue. a (i) BCN057 treatment did not rescue human malignant colonic organoids from radiation toxicity. Organoids derived from surgical specimens of colon tumor were exposed to irradiation (IR; 8 Gy) and then treated with BCN057. Note the loss of the budding crypt-like structure in irradiated organoids treated with BCN057. Treatment with BCN057 in unirradiated organoids also showed the loss of the budding crypt-like structure, indicating that BCN057 has an inhibitory effect on the growth and proliferation of malignant organoids. (ii) The effect of BCN057 treatment on the growth of irradiated crypt organoids developed from human colon tumor. Budding crypts to total crypt ratio reduced in a dose-dependent manner following irradiation (2–8 Gy). A similar pattern of budding crypts to total crypt ratio was observed in irradiated organoids with BCN057 treatment, indicating that BCN057 could not reduce the radiation toxicity in malignant colonic organoids. b BCN057 does not have radioprotective effect on mice abdominal tumors. (i) Representative image of C57BL/6 mice having MC38 colon tumor in the flank at day 20 post-abdominal irradiation (AIR). Note the reduction in tumor size in irradiated or unirradiated tumor treated with BCN057. Mice exposed to AIR without BCN057 treatment are not included in this image as they died within 12 days of AIR. (ii) Tumor growth curve demonstrating the effect of BCN057 treatment on mice abdominal MC38 tumors. Note the significant reduction in tumor growth in BCN057-treated mice following AIR compared with unirradiated untreated controls (p < 0.0004). BCN057 treatment in unirradiated mice also reduces the tumor growth compared with unirradiated untreated controls (p < 0.0007; n = 10/group). The tumor growth curve in the AIR group was discontinued as all mice died from radiation toxicity by day 12 post-radiation. (iii) Kaplan-Meier survival analysis of C57BL/6 mice (n = 10/group) with MC38 abdominal tumors receiving AIR, AIR + BCN057, BCN057, or no treatment. Please note that in the AIR control group all the mice died within 12 days post-radiation. Therefore, the tumor growth curve (ii) is not complete in these mice. Mice receiving BCN057 after 15 Gy AIR demonstrated 60% survival beyond day 20 post-irradiation (p < 0.0006; log-rank (Mantel-Cox) test). Untreated unirradiated control mice (blue line in the graph) were euthanized on day 20 as their tumor volume reached 2000 mm³ (the upper limit of tumor volume approved by the IACUC)